The NIEHS Superfund Research Program: 25 Years of Translational Research for Public Health Philip J

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The NIEHS Superfund Research Program: 25 Years of Translational Research for Public Health Philip J. Landrigan,1 Robert O. Wright,1 Jose F. Cordero,2 David L. Eaton,3 Bernard D. Goldstein,4 Bernhard Hennig,5 Raina M. Maier,6 David M. Ozonoff,7 Martyn T. Smith,8 and Robert H. Tukey9 1Icahn School of Medicine at Mount Sinai, New York, New York, USA; 2University of Puerto Rico Graduate School of Public Health, San Juan, Puerto Rico; 3School of Public Health, University of Washington, Seattle, Washington, USA; 4Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; 5University of Kentucky College of Agriculture, Food and Environment, Lexington, Kentucky, USA; 6Department of Soil, Water and Environmental Science, University of Arizona, Tucson, Arizona, USA; 7Boston University School of Public Health, Boston, Massachusetts, USA; 8School of Public Health, University of California, Berkeley, Berkeley, California, USA; 9University of California, San Diego, La Jolla, California, USA

petroleum industries, the two major producers Background: The Superfund Research Program (SRP) is an academically based,multidisciplinary,­ of toxic wastes. Many of the new sites then translational research program that for 25 years has sought scientific solutions to health and being recognized were the result of actions environmental problems associated with hazardous waste sites. SRP is coordinated by the by parties long gone. The purpose of the tax National Institute of Environmental Health Sciences (NIEHS). It supports multi-project grants, undergraduate and postdoctoral training programs, individual research grants, and Small Business was to provide resources to remediate these Innovation Research (SBIR) and Technology Transfer Research (STTR) grants. orphaned sites. One of the first actions taken under Results: SRP has had many successes: discovery of arsenic’s toxicity to the developing human central nervous system; documentation of benzene toxicity to hematologic progenitor cells in the Superfund Act was the expenditure of human bone marrow; development of novel analytic techniques such as the luciferase expression more than $100 million to clean up dioxin- assay and laser fragmentation fluorescence spectroscopy; demonstration that PCBs can cause contaminated waste oil that had been developmental neurotoxicity at low levels and alter the genomic characteristics of sentinel animals; dumped to control dust on dirt roads in the elucidation of the neurodevelopmental toxicity of organophosphate insecticides; documentation rural community of Times Beach, Missouri. of links between antimicrobial agents and alterations in hormone response; discovery of biological The U.S. EPA purchased the entire town for mechanisms through which environmental chemicals may contribute to obesity, atherosclerosis, $35 million and then bulldozed it down. diabetes, and cancer; tracking the health and environmental effects of the attacks on the World Huge incinerators were built to burn not Trade Center and Hurricane Katrina; and development of novel biological and engineering only all of the homes and belongings in the techniques to facilitate more efficient and lower-cost remediation of hazardous waste sites. community, but the topsoil from the dirt Conclusion: SRP must continue to address the legacy of hazardous waste in the United States, roads (Hernan 2010). respond to new issues caused by rapid advances in technology, and train the next generation of The Superfund tax on the oil and leaders in environmental health science while recognizing that most of the world’s worst toxic hot chemical industries expired in 1995. Today, spots are now located in low- and middle-income countries. cleanup of hazardous waste sites is funded Citation: Landrigan PJ, Wright RO, Cordero JF, Eaton DL, Goldstein BD, Hennig B, Maier RM, through general tax revenues, but the other Ozonoff DM, Smith MT, Tukey RH. 2015. The NIEHS Superfund Research Program: 25 years important components of CERCLA have of translational research for public health. Environ Health Perspect 123:909–918; http://dx.doi. org/10.1289/ehp.1409247 survived. In 1986, major enhancements were put in place via the Superfund Amendments and Reauthorization Act (SARA) of 1986 Introduction sludge to bubble up into the basements of (U.S. EPA 1986), the version of the law Twenty-five years ago, the U.S. Congress the overlying homes. Waste chemicals also currently in force. The U.S. EPA was assigned first set aside funds to address fundamental contaminated nearby streams. By the time responsibility for identifying, listing, cleaning research needs for the nation’s hazardous it was recognized as a hazardous waste site, up, and remediating hazardous waste sites waste problem with the Comprehensive Love Canal contained an estimated 21,000 through its Office of Solid Waste and Environmental Response, Compensation, tons of discarded chemicals consisting of Emergency Response (OSWER). The list and Liability Act (CERCLA) of 1980 [U.S. “caustics, alkalines, fatty acids and chlorinated was known as The National Priorities List Environmental Protection Agency (EPA) hydrocarbons” and was linked to a high rate (NPL) (U.S. EPA 2013b). A new agency, 2011]. At the time, the United States was of miscarriages, birth defects, and other health the Agency for Toxic Substances and Disease galvanized by the discovery of a massive disorders in surrounding neighborhoods (New Registry (ATSDR), was created under the act chemical waste disposal site at the Love Canal York State Department of Health 1981). and assigned responsibility for conducting in Niagara Falls, New York (New York State Within a few years a second major waste site health assessments of populations living near Department of Health 1981), an event that was discovered near Louisville, Kentucky. hazardous waste sites, with special emphasis forcefully put the legacy of many years of Known as the “Valley of the Drums,” the site on children. ATSDR is co-located in Atlanta, improper waste disposal on the public agenda. contained thousands of 55-gal drums full of Georgia, with the Centers for Disease The Love Canal, an unused conduit between chemical wastes that had accumulated over Control and Prevention (CDC). Lake Erie and Lake Ontario, had been used many decades. by the Hooker Chemical Company (later At that time, it became clear to policy Address correspondence to P.J. Landrigan, a subsidiary of the Occidental Petroleum makers and the American public that Department of Preventive Medicine, Icahn School of Company) since the 1940s as a dumping hazardous waste was an environmental Medicine at Mount Sinai, One Gustave L. Levy Place, ground for toxic waste. Once filled with and public health emergency. In response, Box 1057, New York, NY 10029 USA. Telephone: chemical waste, the canal was covered with the U.S. Congress passed CERCLA on (212) 824-7018. E-mail: [email protected] a clay seal in 1953, and homes and a school 11 December 1980. This law became known The authors declare they have no actual or potential competing financial interests. were built atop it. The waste did not stay as the Superfund Act because it authorized Received: 22 September 2014; Accepted: 12 May underground. The canal filled with water, and the creation of a large fund supported by a 2015; Advance Publication: 15 May 2015; Final by 1976 heavy rains regularly caused toxic tax on the chemical manufacturing and Publication: 1 October 2015.

Environmental Health Perspectives • volume 123 | number 10 | October 2015 909 Landrigan et al.

The Superfund Research Program (SRP). One unique aspect is the requirement for that can be applied in the United States. For SRP was launched in 1987. It was established an integrated suite of research projects that example, the UC San Diego SRP represents by the Congress to provide scientific support includes a minimum of two biomedical SRP on the Good Neighbor Environmental for the U.S. EPA and ATSDR hazardous projects and two environmental science or Board (GNEB), an independent federal waste programs and funded through a small engineering projects (Suk and Anderson advisory committee that provides guidance set-aside from the Superfund Trust. SRP’s 1999; Suk et al. 1999). There may be as to the President and the Congress on envi- mission is to “seek solutions to the complex many as 12 components organized around a ronmental challenges along the U.S.–Mexico health and environmental issues associated common theme and supported by core facili- border (U.S. EPA 2014). Another major with the nation’s hazardous waste sites with ties. The mandatory pairing of environmental SRP presence on the U.S.–Mexico border the ultimate goal of improving public health.” research with biomedical research is unique in is the Dean Carter Binational Center for It has worked to provide answers to impor- the NIH portfolio. Environmental Health Sciences, a partner- tant scientific questions: How clean must a Each SRP must include a) an ship between the University of Arizona, UC site be? And how might a site be remediated Administrative Core that promotes cross- San Diego, and Texas A&M SRPs and 11 to maximum effect and at minimum cost? disciplinary interactions, and is responsible Mexican universities and research institutes Chemical mixtures posed a particular chal- for oversight and liaison; b) a Research (University of Arizona 2014). Its goal is to lenge because hazardous waste sites often Translation Core that disseminates informa- stimulate innovative cross-border research, contain complex collections of chemicals, and tion to other scientists, policy makers, and community engagement, and education (U.S. unexpected interactions can lead to unfore- the public, helping to transform scientific EPA and Secretaría de Medio Ambiente y seen forms of toxicity. discoveries into applications that can inform Recursos Naturales 2012). The Columbia In this report we present a summary of the risk assessment and guide site remediation University SRP has extensively studied the first 25 years of SRP. It is based on remarks and disease prevention; c) a Community epidemiology and toxicology of arsenic in presented at the Twenty-Fifth Annual SRP Engagement Core that builds partnerships Bangladesh (Ahsan et al. 2006), the Harvard Meeting [National Institute of Environmental with affected communities (Pezzoli et al. SRP has studied the consequences of lead Health Sciences (NIEHS ) 2012]. 2007); and d) a Training Core, essential for exposure in Mexico (Gomaa et al. 2002; Early on, it was decided that, although developing a new generation of scientists Téllez-Rojo et al. 2006), and the UC Berkeley funding for hazardous waste research was schooled in the interdisciplinary­ research SRP has studied the hematopoietic toxicity of appropriated to the U.S. EPA, the research required to solve the complex problems of benzene in China (Smith et al. 2005). program would be administered by the abandoned hazardous wastes. Finally, SRP goes beyond research to National Institutes of Health (NIH) and The SRP also provides funding for indi- actually developing solutions to environ- conducted in the nation’s leading research vidual research grants (R01s) as well as for mental health problems. Much work has gone universities. Accordingly, the NIEHS, a Small Business Innovation Research (SBIR)/ into a) the development of novel technologies component of NIH, was assigned responsi- Small Business Technology Transfer Research for detection of biologically active environ- bility for establishing the program, named (STTR) grants. These Small Business grants mental chemicals, b) an understanding of the initially the NIEHS Superfund Hazardous are designed to foster the commercialization biological basis of environmental chemical Substances Basic Research and Training of relevant technologies and devices. The toxicity, and c) the development of innovative Program (NIEHS 1987). R01 program is dedicated to relevant envi- remediation technologies to help clean up In the early years of the program, research ronmental research. A parallel program at Superfund and other hazardous waste sites. funds were awarded to EPA and then “passed NIEHS, also funded by the Superfund appro- The following are examples. through” to NIEHS. Later, to enhance priation, supports a national worker training New detection technologies. Detection administrative efficiency, this arrangement was curriculum and has trained 1.4 million of aryl hydrocarbon agonists. Halogenated changed to a “line item” budget allocation in hazardous waste workers. aromatic hydrocarbons (HAHs) are highly the annual budget for NIEHS. The heightened vulnerability of children toxic and are found commonly in industrial From its outset, SRP has been guided to environmental health threats is a theme waste. Michael Denison of the UC Davis SRP by a clear vision set by its founding director, long emphasized by SRP [National Research developed a new approach to track HAH and William Suk, and nurtured and encour- Council (NRC) 1993; U.S. EPA 1996]. This related dioxin-like chemical ­contaminants aged by a succession of NIEHS Directors, emphasis has resulted in extensive support for (Denison et al. 1998). starting with David Rall and followed by research in children’s environmental health Using cultured cells, Denison manipulated Kenneth Olden, David Schwartz, Interim (Landrigan et al. 1999), exemplified by the the aryl hydrocarbon receptor system, the Director Sam Wilson, and current Director, fact the NIEHS’s national network of Centers intricate biological mechanism that responds Linda Birnbaum. William Suk remains the for Children’s Environmental Health and to HAHs, to create a highly specific, sensi- SRP Director, accounting for the stability and Disease Prevention Research had its origins tive, and low-cost method for tracking dioxins steadiness of the program (Wilson 2014). within the UC Berkeley SRP. Several NIEHS and other HAHs (U.S. EPA and Secretaría de In 1987, the first year of the program, Children’s Environmental Health programs Medio Ambiente y Recursos Naturales 2012). four Universities were funded: University are now co-located in universities with This bioassay uses aryl hydrocarbon receptor of California (UC), Berkeley; UC Davis; SRP programs. signaling to link HAH contamination to the University of Washington; and Massachusetts In recent years, as the world’s most heavily production of a fluorescent luciferase reporter. Institute of Technology (MIT). Today, SRP polluted places come increasingly to be A further advantage of this bioassay is that supports research in 18 university-based located in low- and middle-income ­countries it responds to HAH in a dose-dependent Centers across the United States. These Centers (Blacksmith Institute 2013), SRP has directed manner, and thus the relative brightness of the are selected through rigorously ­independent substantial resources to study those environ- luciferase glow reflects the level of HAH-like and highly competitive peer review. ments. These efforts, undertaken in partner- activity. This work led to the development What appears at first sight to be a ship with local universities and government of the Chemical Activated LUciferase gene conventional multi-project research struc- agencies, seek to remediate problems in eXpression (CALUX®) system (Rogers and ture is in reality anything but conventional. developing countries and also to learn lessons Denison 2000; Windal et al. 2005) now

910 volume 123 | number 10 | October 2015 • Environmental Health Perspectives The NIEHS Superfund Research Program used by the U.S. EPA to evaluate HAH in Bangladesh to investigate and control process, but Vas Aposhian and colleagues ­contamination in environmental media. health problems caused by chronic exposure showed that methylated metabolites of arsenic Detection of xenoestrogens. In August to arsenic (Ahsan et al. 2006). HEALS is were, in fact, more toxic to cells than inor- 2012, the BG1Luc assay, developed by providing important data on arsenic toxicity ganic arsenic (Petrick et al. 2001). These Xenobiotic Detection Systems Inc., a system across a wide range of exposure levels. A researchers showed that the monomethylated similar to the Denison system, and developed major finding is that chronic exposure to metabolite of arsenic [monomethylarsonous with support from an SRP SBIR grant, was relatively low levels of arsenic is associated acid (MMAIII)] can be detected in urine accepted as part of EPA’s Tier 1 screening with an increase in overall mortality (Argos (Marnell et al. 2003) and can be used to profile program for estrogenic chemicals (Gordon et al. 2010). ethnic differences in the regulation of MMAIII and Clark 2005). This assay provides a Another major finding is that prenatal production (Gomez-Rubio et al. 2012) as well platform for testing the endocrine-disrupting exposure to arsenic in drinking water is nega- as differences in body composition and lifestyle activity of various compounds. It is based on tively associated with brain development in (Gomez-Rubio et al. 2011). hormone-stimulated transcriptional regulation children (Wasserman et al. 2011). This study, To investigate whether MMAIII is involved and uses cultured cells that express estrogen led by Joseph Graziano, found significant in the causation of bladder cancer, University receptors. When these receptors are stimulated evidence for a negative dose–response relation- of Arizona SRP researcher A. Jay Gandolfi by estrogenic compounds acting as agonists ship between arsenic exposure and childhood exposed cultured human bladder cells to or antagonists, they modulate the expression intelligence. The study found also that early- MMAIII at a concentration found in the urine of an estrogen promoter–regulated luciferase life exposure to arsenic affects motor function of arsenic-exposed populations. He found reporter gene. (Parvez et al. 2011). Children exposed to water that this exposure did indeed cause cellular Real-time analysis of multiple compo- arsenic concentrations > 10 μg/L performed changes consistent with malignant transforma- nents in exhaust. A team of SRP researchers, more poorly on tests of intelligence and motor tion (Eblin et al. 2008). Subsequent studies led by Catherine Koshland at UC Berkeley, function than those exposed to < 10 μg/L. The found that MMAIII imprinted cultured human collaborated with scientists at Lawrence present EPA drinking water standard for the bladder cells early in their continuous exposure Berkeley National Laboratory to develop an United States is 10 μg/L (10 ppb) (U.S. EPA (Wnek et al. 2010). These changes were shown entirely new technique for real-time, contin- 2013a), and many regions around the world, to be irreversible and to be associated with uous monitoring of compounds commonly including some areas of the United States, still changes in the epigenome (Jensen et al. 2009), found in combustion effluents. have arsenic drinking water concentrations well cytokine signaling (Escudero-Lourdes et al. The technique uses excimer laser fragmen- above this standard. 2010), and global gene expression (Medeiros tation fluorescence spectroscopy to detect and The Columbia University team has lever- et al. 2012). quantify multiple components in combustion aged additional resources to provide basic Benzene. To increase mechanistic under- exhausts (Avakian et al. 2002). High-energy primary medical care to 20,000 people in standing of benzene carcinogenicity, Stephen photon beams fragment the contaminants rural Bangladesh. Before the team arrived, Rappaport, an exposure scientist, who was that can then be optically detected by laser- there were no physicians there. Now the then at the University of North Carolina at induced fluorescence. The method can simul- clinic has its own pharmacy and has capacity Chapel Hill SRP, and Martyn Smith, a molec- taneously detect multiple airborne elements to perform X-rays and electrocardiograms, ular toxicologist at the UC Berkeley SRP, and compounds down to very low levels (in and to provide dental care along with primary developed and applied novel biomarkers of the parts per billion range), including chlo- health care (States et al. 2009). benzene exposure and at the same time inves- rinated hydrocarbons, barium, chromium, SRP research has demonstrated that tigated benzene-associated changes in DNA. manganese, nickel, lead, and tellurium. The arsenic exposure remains an important health Rappaport and Smith have measured assay detects chemicals in real time and also issue in the United States. Margaret Karagas biomarkers in several hundred benzene- in situ (Choi et al. 2005). of the Dartmouth College SRP has led studies exposed workers and unexposed control Before this invention, the standard in the northeastern United States showing subjects (Smith et al. 2005). They observed practice for monitoring combustion by-prod- correlations between arsenic exposure in water that low levels of exposure to benzene—levels ucts involved lengthy, labor-intensive sample and skin and bladder cancer (Karagas et al. < 1 ppm—cause a reduction in the number extractions and preparations that could 2002). Subsequent studies profiled the mecha­ of circulating white blood cells and that require several weeks. nisms for the arsenic-associated health effects benzene exposure is also toxic to hematologic Understanding the biological basis of envi- including hypermethylation (Marsit et al. progenitor cells, the unspecialized cells in the ronmental chemical toxicity. Arsenic. Arsenic 2006a), DNA repair (Andrew et al. 2006), human bone marrow from which all blood is a natural contaminant of groundwater epigenetics (Marsit et al. 2006b), and genetic cells develop (Zhang et al. 2012). This finding in nearly 70 countries around the world, polymorphisms (Karagas et al. 2012). is very significant because the current occu- including areas of the United States. It is also Studies from the Dartmouth SRP were the pational exposure standard for benzene in released to the environment by industrial first to report the presence of arsenic in rice the United States and in many other coun- processes such as mining, fossil fuel extrac- and showed that rice consumption contrib- tries is a time-weighted average exposure of tion, and hydraulic fracturing for natural gas. utes to arsenic exposure among women in 1 ppm. Rappaport et al. (2010) also found Arsenic is a proven human carcinogen. It the United States (Gilbert-Diamond et al. that benzene metabolite exposure biomarkers also causes cardiovascular and other chronic 2011). These researchers found elevated levels increase with increasing air concentrations, diseases (States et al. 2009). of arsenic in brown rice syrup used in many but in a nonlinear fashion, suggesting that Bangladesh is very severely affected processed foods, including many infant foods cytochrome P450 metabolism of benzene is by arsenic in groundwater. An estimated (Jackson et al. 2012). saturated at relatively low exposure levels. 35–77 million people in Bangladesh depend The University of Arizona SRP has The development by Rappaport et al. on well water contaminated with arsenic. A examined arsenic biotransformation and (2010) of a comprehensive set of biomarkers multidisciplinary team from the Columbia studied the impacts of arsenic metabolites on enabled these SRP researchers to system- University SRP established the Health Effects human health. Previously it was believed that atically explore benzene–biomarker relation- of Arsenic Longitudinal Study (HEALS) methylation of arsenic was a detoxification ships over a wide range of occupational and

Environmental Health Perspectives • volume 123 | number 10 | October 2015 911 Landrigan et al. environmental exposures. Their work was cited Importantly, these effects were shown to be on the bone microenvironment for growth by EPA in justifying its decision to lower the independent of cholinesterase inhibition, the and differentiation signals. benzene content of gasoline, pointing to supra- primary mechanism for acute OP poisoning, With the understanding that PPAR linear (greater-than-proportional) produc- and occurred at exposure levels below the controls fat (adipogenesis) and bone (osteo- tion of benzene-related protein adducts at air threshold for cholinesterase inhibition. genesis) development, Schlezinger and her concentrations < 1 ppm (U.S. EPA 2007). Slotkin’s research team is also investi- team reasoned that inappropriate activation Lead and metal mixtures. In 1994, gating the toxic effects of OP exposures on of these receptors by organotins might skew a group of Harvard School of Public glucose and lipid metabolism. They found differentiation of a bipotential mesenchymal Health researchers led by Howard Hu initi- that early-life exposures of rodents to chlor- stem cell toward the adipocyte lineage and ated the Early Life Exposure in Mexico to pyrifos, diazinon, or parathion resulted away from the osteogenic lineage (Yanik et al. Environmental Toxicants (ELEMENT) in metabolic profiles resembling the initial 2011). In fact, nanomolar concentrations of cohorts through an SRP grant (Harvard School stages of diabetes (Slotkin et al. 2005). More organotins appear to distort the differentiation of Public Health, Superfund Research Program recently they observed that these exposures of these stem cells so that formation of fat is 2014). The goal of this project was to map the produce sex-selective changes in serum lipids, favored over bone development and repair. adverse effects of lead exposure on early child- leading to increased body weight in adulthood­ Exposures to these chemicals thus resulted in hood development. Mexico City was chosen (Slotkin 2011). premature aging of bone. Furthermore, the as the venue because lead exposure is very Further studies of OPs undertaken at the data suggest a plausible mechanism through high there, reflecting use of leaded gasoline University of Washington SRP led by Clem which organotins could contribute to the accu- until 2000 and widespread use of lead-glazed Furlong and Lucio Costa have studied whether mulation of visceral fat—by inappropriately pottery. Also, this location provided the oppor- common single nucleotide polymorphisms activating the PPAR in other organs. tunity to collaborate with a strong Mexican (SNPs) in paraoxonase 1 (PON1), the gene PCB exposures and infant development. research team. Data from ELEMENT have that detoxifies chlorpyrifos (Shih et al. 1998), Harvard University SRP grantee Susan Korrick confirmed the developmental neurotoxicity of are related to increased susceptibility to cholin- and her research team were among the first lead at low levels, showed that measurement esterase inhibition. They found that the SNP at to find an association between in utero expo- of bone lead content by X-ray fluorescence –108C results in doubling the concentration sures to polychlorinated biphenyls (PCBs) and provides an accurate time-integrated biomarker of PON1 in plasma, relative to the common altered developmental achievement and growth of cumulative lead exposure, and demon- form, –108T. Another SNP, Q192R, increases in infancy and later childhood­ (Sagiv et al. strated that lead from the maternal skeleton the catalytic efficiency of PON1 toward certain 2008, 2012). can be mobilized during pregnancy to increase pesticides (Shih et al. 1998). Their study was performed with a cohort maternal and fetal blood lead levels (Gomaa Furlong and Costa demonstrated that of 900 mother–infant pairs in a community et al. 2002; Téllez-Rojo et al. 2006). PON1 is slow to get “turned on” after birth. adjacent to a PCB-contaminated harbor and In 2006, Robert Wright, also then They have now begun to explore whether Superfund site in New Bedford, Massachusetts. at Harvard, founded a second ELEMENT failure of PON1 to be expressed in early life It revealed that exposure to PCBs may be cohort in Mexico City focused on metal might increase the vulnerability of young associated with adverse effects on fetal matu- mixtures—arsenic, manganese, lead, and children to chlorpyrifos and other OP ration and may therefore be a modifiable risk cadmium. This project is also quantifying insecticides. Their studies found that children factor for premature birth. They also found exposures to social stress and poverty and < 2 years old, especially those homozygous for that infant visual memory, which is predictive exploring the hypothesis that combined expo- PON1Q192, are potentially highly susceptible of cognitive performance in childhood, may sures to metals and social stressors in early to chlorpyrifos toxicity (Furlong et al. 2005). also be impaired by in utero PCB exposure. life have synergistic adverse effects on neuro- Organotins as environmental obesogens. The researchers examined the children development. To date, the new ELEMENT A team of SRP investigators at Boston again when they were 8 years old. This follow- study has detected a consistent pattern of University, led by Jennifer Schlezinger, has up investigation revealed that early-life expo- adverse effects on development from both lead used innovative techniques to assess plau- sures to PCBs were consistently associated and social stress. It has also found that the sible mechanisms through which organo- with adverse behaviors, particularly behaviors disturbed salivary cortisol rhythms that follow tins, used in anti-fouling paint on the hulls associated with attention deficit/hyperac- high levels of stress are associated with adverse of ships, could stimulate formation of fatty tivity disorder (ADHD). They observed that development (Braun et al. 2014). bone tissue and degradation of structural sociodemographically disadvantaged children Organophosphate neurotoxicity. bone (Bissonnette et al. 2010). Organotins were especially susceptible (Sagiv et al. 2012). Theodore Slotkin at the Duke University SRP are now ubiquitous in marine environments. These findings are notable because, is studying the effects on brain development Schlezinger demonstrated that extremely although the cohort lives adjacent to a and metabolism of exposures in early life to low doses of organotins adversely affect the PCB-polluted harbor, PCB exposure levels widely used organophosphate (OP) pesticides. development­ of B lymphocytes in the bone in this population are similar to those found Data from Slotkin’s lab show that early- marrow through activation of the peroxi- in other populations across the United States. life OP exposure results in reduced numbers some proliferator–activated γ receptor This suggests that the developmental neuro- of neurons and in neurobehavioral deficits (PPARγ) and the retinoid X receptor (RXR) toxicity of PCBs may occur at exposure levels (Slotkin et al. 2006). To elucidate the under- (Yanik et al. 2011). Because this cell subset found commonly. lying mechanisms, the Slotkin team evaluated matures into blood lymphocytes responsible PCB exposure and genetic variation in gene expression in newborn rodents that had for generating protective antibodies, the sentinel animals. An outstanding example been exposed to low levels of the OP insecti- results strongly suggested that organotins of collaboration among SRP investigators cides chlorpyrifos and diazinon during the first could act as immuno­suppressants. Perhaps is provided by a study undertaken by the 4 days of life. They found that chlorpyrifos and more important, the data also suggested that Boston University SRP in partnership with diazinon each resulted in changes in expression organotins have global effects on the bone Mark Hahn, a senior scientist at the Woods of 20–25% of genes related to cell cycle and microenvironment and on the development Hole Oceanographic Institution. Hahn has apoptosis pathways (Slotkin and Seidler 2012). and function of other cell types that depend been using populations of fish in the New

912 volume 123 | number 10 | October 2015 • Environmental Health Perspectives The NIEHS Superfund Research Program

Bedford Harbor Superfund site to study the environmental health. Pharmacokinetic termed PROTECT—Puerto Rico Testsite effects of environmental chemical exposure studies in humans have shown that TCC in for Exploring Contamination Threats—are on genetic variation. He is trying to under- commercial soap is rapidly absorbed through José Cordero of the University of Puerto stand the genetic impacts of long-term, the skin and easily detectable in urine within Rico, Akram Alshawabkeh of Northeastern multi-generational exposure to high levels 72 hr (Schebb et al. 2011). University, and John Meeker and Rita of dioxin-like chemicals on fish. Specifically, Bruce Hammock in the UC Davis SRP Loch-Caruso of the University of Michigan. he is studying a population of estuarine fish, has provided evidence in cell-based bioassay Preterm birth is a serious global public health Atlantic killifish (Fundulus heteroclitus). Hahn screens that TCC and TCS modify the problem that accounts for nearly 1 million demonstrated that New Bedford Harbor estradiol- or testosterone-dependent activation infant deaths each year worldwide. Puerto killifish are much less sensitive to dioxin- of the estrogen receptor (ER) and the androgen Rico has the highest density of NPL sites like compounds than are killifish from an receptor (AR) (Morisseau et al. 2009). In a per square mile and also the highest rate uncontaminated reference site on Cape Cod collaboration with the UC San Diego SRC, of preterm birth of any U.S. jurisdiction and that this chemical resistance is heritable Hammock and his team found that TCC (Callaghan et al. 2006). through several generations (Harbeitner et al. treatment of mice activated both the constitu- John Meeker from the University of 2013; Oleksiak et al. 2011). He and his team tive androstane receptor and ERα, leading to Michigan showed that urinary phthalate have demonstrated that the gene pool of a downstream induction of target genes (Yueh metabolite concentrations were higher among highly exposed animal can be dramatically et al. 2012). Hammock and his colleagues preterm births in Puerto Rico than controls. and possibly permanently changed following have recently shown that TCS alters type 1 He also found evidence for a positive dose– chronic exposure to PCBs. ryanodine receptor (RyR1) activity and response relationship between preterm birth Superfund chemicals, liver damage, impairs physiological excitation–contraction and exposures to some phthalates (Meeker and hepatocellular carcinoma. To examine coupling in both cardiac and skeletal muscle et al. 2009). Meeker conducted a follow-on the cellular and molecular mechanisms (Cherednichenko et al. 2012). TCC was also study using a nested case–control design in a though which Superfund chemicals may shown to be a potent inhibitor of soluble much larger group of women that included cause liver damage and hepatocellular epoxide hydrolase, which has been linked to 130 mothers who had delivered at < 37 weeks carcinoma, Michael Karin and his team in anti-inflammatory activity (Liu et al. 2011). of completed gestation and 352 control the UC San Diego SRP are studying envi- These findings provide important mothers who delivered at ≥ 37 weeks. They ronmental chemicals known to be mutagens. evidence that TCC and TCS can alter impor- found that women with the highest levels of They found that initial injury to liver cells tant hormonal signaling pathways in animals phthalate exposure during pregnancy had following exposures to these chemicals results and humans. These data moved the Food and up to five times the likelihood of preterm in the generation of reactive oxygen species Drug Administration to recently reevaluate birth compared with women with the lowest (ROS) (Sakurai et al. 2008). They further the benefit–risk ratio of using these agents in exposure (Ferguson et al. 2014). These discovered that the IKK/NF-κB (I κB kinase/ personal care products. findings will be further explored in a longi- nuclear factor κB) inflammatory pathway Nutritional modulation of Superfund tudinal cohort of nearly 800 pregnancies in within cells is critical to controlling levels of pollutant toxicity. The University of Kentucky Puerto Rico. ROS (Karin and Greten 2005; Sakurai et al. SRP studies mechanisms through which nutri- Health consequences of disasters. 2006). In mice whose IKKβ in liver had been tion can modulate environmental insults. Following the 11 September 2001 (9/11) deleted, they demonstrated that ROS levels Dietary habits and particular foods are known terrorist attacks on New York City, SRP are increased. The consequence was high levels to enhance and also to protect against the awarded emergency supplemental funding of apoptosis and cell death (He et al. 2010). health impacts of exposures to environmental to the Mount Sinai School of Medicine SRP Additionally, they found that these mice are pollutants (Hennig et al. 2007). to study the health effects of the toxic envi- at much higher risk of developing hepatocel- Bernhard Hennig and his colleagues at ronmental exposures that resulted from the lular carcinoma when the mice are exposed Kentucky have shown that diets rich in proin- destruction of the World Trade Center. to Superfund chemicals with mutagenic flammatory fatty acids (e.g., omega-6 fatty Three programs were launched: a) clinical potential (Sakurai et al. 2006). These findings acids) can exacerbate PCB-induced vascular and epidemiological studies of emergency document that NF-κB is a critical mechanistic endothelial activation and atherosclerosis response workers who served at Ground link between the onset of inflammation, liver (Hennig et al. 2002, 2005). In contrast, anti- Zero, b) a prospective follow-up study of toxicity, and long-term risk of cancer. oxidant and/or anti-inflammatory nutrients 182 pregnant women who were inside or near Further experiments conducted in the (e.g., omega-3 fatty acids and plant-derived the World Trade Center at the time of the Karin laboratory have led to the discovery polyphenols) protect against PCB toxicity attacks, and c) a pediatric outreach program. that in the presence of liver damage caused (Majkova et al. 2011; Newsome et al. 2014). These studies were launched in close coor- by mutagenic chemicals frequently found at Nutritional modulation of disease dination with the National Institute for Superfund sites, obesity can serve as a potent outcomes associated with exposure to Occupational Safety and Health and the promoter of hepatocellular carcinoma (He Superfund pollutants is particularly important New York City Department of Health and et al. 2013; Park et al. 2010). This finding during critical developmental phases in early Mental Hygiene. is of great significance for public health childhood. Much information is emerging Two parallel occupational studies—one given the high prevalence of obesity in the related to epigenetic mechanisms involved in led by David Prezant that is following New United States. these processes (Hennig et al. 2012). York City Fire Department firefighters and Antimicrobials and endocrine disrup- Phthalates and preterm births. One of paramedics, and the other by Philip Landrigan tion. Triclosan (TCS) and trichlocarban the newest SRP Programs, at the University that is following the remainder of the 9/11 (TCC) are chlorinated phenols widely used of Puerto Rico in partnership with SRP responder population—found that workers as antimicrobials in personal care products researchers at Northeastern University and at Ground Zero developed new-onset cough, such as soaps and disinfectants. TCC and the University of Michigan, is exploring wheeze, and phlegm production in the TCS currently contaminate many waterways possible links between environmental factors initial weeks and months after the attacks and are of growing concern to human and and preterm births. Leaders of this program, (Landrigan et al. 2004; Weakley et al. 2011).

Environmental Health Perspectives • volume 123 | number 10 | October 2015 913 Landrigan et al.

These symptoms were most likely caused by plant converts these elements to mercury (Lewis et al. 2011). The device could offer inhalation of massive quantities of the highly sulfide, which has high stability and low solu- an inexpensive way to provide clean drinking alkaline dust (pH 10–11), which caused bility. Their work has focused primarily on water in areas of the world where chemical intense inflammation and subsequent scarring wet ecosystems and has demonstrated high contamination is prevalent. The system uses and distortion of airways. Ten-year follow- levels of mercury uptake by rabbit-foot grass nanostructured materials to generate hydroxyl up assessment of this population found that to concentrations up to 110 times that of a radicals that can remove the contaminants. despite a very low prevalence of tobacco control plant. Bhattacharyya’s group also pioneered smoking, 41% had persistently impaired A multidisciplinary team from the the synthesis of iron-based nanoparticles for pulmonary function, most commonly restric- University of Arizona SRP, led by envi- toxic organic de-chlorination using “greener” tive impairment. Pulmonary impairment and ronmental microbiologist Raina Maier and approaches and responsive polymer membrane other abnormal findings were most frequent biogeochemist Jon Chorover, is using a platform (Meeks et al. 2012). and severe in workers experiencing the heaviest phytoremediation approach to treat mining Lindell Ormsbee and the University of exposure (Wisnivesky et al. 2011). Mental wastes. These wastes are prevalent in arid and Kentucky SRP Research Translation Core health symptoms were also common and they semi-arid environments and can be highly worked with Bhattacharyya to find ways to too showed an exposure–response gradient. contaminated with arsenic, lead, and other implement his technology at the Paducah The major finding in the study of pregnant toxic metals. The team is using native plants Gaseous Diffusion Plant, Kentucky’s largest women led by Gertrud Berkowitz of Mount that do not accumulate metals into shoot Superfund site, which contains significant Sinai was that the rate of intrauterine growth tissues to establish a vegetative cap and stabilize contamination by TCE and PCB (Gui et al. restriction doubled in infants born to mothers metals in the rooting zone—a process called 2013; Meyer et al. 2009). who were inside or near the World Trade phytostabilization (Mendez and Maier 2008). Groundwater remediation. Mark Center on 9/11, compared with unexposed They have combined cutting-edge molecular Brusseau and his research group at the controls in the New York City area (Berkowitz ecology and geochemistry techniques to University of Arizona SRP have conducted et al. 2003). examine the plant root–microbe–tailings envi- an extensive, two decades–long, research SRP also provided emergency supple- ronment and the complex transitions that take program, comprising field tests, mathematical mental funding to study health effects in the place during revegetation. They are developing modeling studies, and laboratory investiga- aftermath of Hurricane Katrina. Working biogeochemical indicators to predict vegetation tions, focused on the Tucson International through the NIEHS Portal, which combines success. Major mining companies have part- Airport Area Superfund site (NRC 2013). advances in geographic information systems, nered with this research team and will use these This program has investigated the transport data mining/integration, and visualization data to guide revegetation strategies. and fate of chlorinated-solvent contaminants technologies, SRP investigators were able to To further boost the phytoremediation in groundwater, while addressing issues critical provide decision makers in the Gulf Coast potential of plants, information is needed to the characterization and remediation of region with the data, information, and the about the mechanisms and pathways that hazardous waste sites (NRC 2013). tools they needed to a) monitor human and mediate the uptake, detoxification, and These researchers have also developed and environmental health impacts of Hurricane sequestration of toxic heavy metals (Mendoza- tested several innovative methods for char- Katrina; b) assess and reduce human exposures Cózatl et al. 2011; Song et al. 2010). Julian acterization and remediation of subsurface to contaminants; and c) develop science-based Schroeder’s laboratory at the UC San Diego contamination. For example, the first full- remediation, rebuilding, and repopulation SRP has identified several of the genes and scale application of the partitioning tracer strategies (Miranda 2007). proteins in plant vacuoles responsible for these test method for detecting organic-liquid Innovative remediation technologies. actions. They function via ABC transporters contaminants in the subsurface was tested at Phytoremediation. Phytoremediation is the and long-distance root-to-shoot transport the site. In addition, some of the initial field use of plants to remove, detoxify, or stabilize mechanisms (Mendoza-Cózatl et al. 2011; applications of the integrated contaminant toxic chemicals in contaminated soils and Song et al. 2010). mass discharge test, the multi-solute diffusive groundwater. It represents a very attrac- Schroeder also discovered that a sodium tracer test, and the bioactive tracer test were tive alternative to conventional remediation metal transporter was key in protecting conducted at the site (Brusseau et al. 2013). technologies, which are expensive and time plants from salt stress, known to be a major Solar-powered electrochemical remedia- consuming and can produce toxic by-products. factor in crop losses (Schroeder et al. 2013). tion. A team of researchers at the Northeastern The late Milton Gordon and Lee Newman Translating these findings to other investiga- University SRP, led by Akram Alshawabkeh, of the University of Washington SRP applied tors in Australia, the sodium transporters have developed a solar-powered electrochemical plant physiology, cell culture techniques, been genetically engineered into wheat plants technology to manipulate the chemistry of agronomy, microbiology, hydrogeology, and that are highly tolerant of ground salt. The groundwater, enabling in situ treatment of engineering to design a phyto­remediation outcome of this discovery, which was initiated contaminants (Alshawabkeh and Mao 2012). strategy for hazardous waste sites where through SRP efforts, has been an increase in The technology uses solar panels to apply low- groundwater is contaminated with organic wheat production of over 25%. By improving level direct electric currents through electrodes solvents. They found that hybrid poplar salt tolerance, important crops such as wheat in wells, manipulating the groundwater chem- trees can detoxify organic solvents such as can be grown on previously used farmland istry through electrolysis to create conditions trichloroethylene (TCE), perchloroethylene, that has been claimed to be fallow due to favorable for either reduction or oxidation of and carbon tetrachloride that have become salination. Such advances could eventually contaminants. The process is versatile and can widespread industrial pollutants (Gordon increase the world’s production of wheat and treat a mixture of chemicals including TCE, et al. 1998). improve our planet’s food production. dichromate, selenite, nitrate, and phosphate. SRP SBIR grantee Edenspace Systems Nanotechnology. Dibakar Bhattacharyya This technology offers several advan- Corp. is exploiting the ability of rabbit-foot and other scientists at the University of tages: a) It is driven by a renewable energy grass (Polypogon monospeliensis) to remove Kentucky SRP developed a double-membrane source, b) it is environmentally friendly mercury and sulfur from contaminated soils remediation system that removes chlorinated because it does not require the addition of (Edenspace Systems Corporation 2014). The organic contaminants from groundwater chemicals into groundwater, and c) rates

914 volume 123 | number 10 | October 2015 • Environmental Health Perspectives The NIEHS Superfund Research Program of redox (oxidation-reduction) reactions border, Donnelly stressed the importance hazardous waste sites (U.S. EPA 1996). In can be controlled by adjusting electric of learning coupled with community-based the United States, these populations include current intensity. research as he worked to improve the lives of the 11 million people who live within 1 mile Training programs. Training programs poor and disenfranchised border populations of a federal Superfund site, the many others that educate the next generation of leaders in exposed to hazardous waste. who live in proximity to state Superfund sites, environmental health science have been an and the many thousands of hazardous waste essential component of SRP since its incep- Discussion workers and emergency responders who work tion. Each academically based SRP is required The problem of hazardous waste, though much at these sites or respond to fires and other to contain a training program that supports better controlled in the United States today emergencies at them. graduate- and postdoctoral-level cross-disci- than in the past, has not gone away. New Children living in communities near plinary training in fields related to environ- chemicals and new technologies are invented hazardous waste sites are at especially high risk mental health and environmental science every year (Landrigan and Goldman 2011). because their unique patterns of exposure and and engineering. SRP regards these training New forms of waste are created. Hazardous heightened biological vulnerability increase programs as a vital for the mentorship, educa- chemical and nuclear wastes continue to pose the likelihood that they will be exposed to tion, and training of environmental health and major threats to the environment and to public toxic chemicals and suffer adverse health science professionals. health. Laws and regulations on chemical effects (Landrigan et al. 1999; NRC 1993). Over the past 25 years, SRP has trained safety are relatively weak (Landrigan and Poor and minority populations are at high a total of 1,504 trainees in 32 institutions. Goldman 2011). risk of exposure because hazardous waste sites Of these, 689 are currently in training, and Hazardous waste and chemical pollution are disproportionately located in neighbor- 815 have completed training. The scientists have also become global issues. Production hoods of lower socioeconomic status and and engineers who have finished their training of synthetic chemicals and the generation predominantly minority demographics—a have pursued a range of careers—267 in of hazardous waste were initially concen- circumstance termed “environmental injus- academia, 45 in government, 143 in industry, trated in high-income countries, reflecting tice” (Faber et al. 2002; United Church of and 49 in other areas. the origins of the chemical manufacturing Christ Commission for Racial Justice 1987). SRP has established two awards for industry in Western Europe in the late 19th The SRP commitment to community outstanding trainees. The Karen Wetterhahn and early 20th centuries and its spread in engagement has allowed for the creation of Memorial Award, established in 1998, recog- the 20th century to North America, Japan, partnerships with community groups most nizes an outstanding young research scientist and Australia. Today, however, the chemical seriously affected by contamination. SRP has conducting research relevant to SRP who manufacturing industry (Goldstein et al. supported the development and use of inno- demonstrates the qualities of scientific excel- 2013) is increasingly globalized, and the vative tools for communication and engage- lence exhibited by Karen E. Wetterhahn manufacture and use of chemicals are shifting ment (Pezzoli et al. 2007). One such tool, (1948–1997), professor of chemistry and increasingly to low- and middle-income coun- created by the Boston University SRP, is a founder of the Dartmouth College SRP. tries, where labor costs are low and environ- guide for community groups (Scammell and Wetterhahn was an internationally recognized mental protections often few. Also, exports to Howard 2015). This guide helps communities chemist who studied mechanisms of metal low-income countries of hazardous materials decide whether a health study is an appro- toxicity. Tragically, she died in 1997 as the such as asbestos (World Health Organization priate strategy for addressing their concerns. result of a laboratory accident in which a few 2014), banned pesticides (Smith et al. 2008), It is freely available and includes contribu- drops of highly toxic liquid dimethylmercury and e-waste (Robinson 2009) are accelerating. tions by residents living near contaminated penetrated her protective latex glove and caused As a result, the threat of hazardous waste is sites, community and agency partners, and rapidly progressive, fatal neurological impair- greatest today in low- and middle-income SRP investigators. A second example is the ment. Wetterhahn was deeply concerned with countries (Caravanos et al. 2011; Grant et al. freely available, transferrable training modules bringing young women into science. She was 2013), and in those countries, hazardous waste developed by the University of Arizona SRP co-founder of the Women in Science Project at has become an important, although insuffi- in collaboration with promoters (Hispanic Dartmouth, a highly successful program where ciently recognized, contributor to the burden community health workers) (University of first-year women engage in learning experiences of disease (Chatham-Stephens et al. 2013). Arizona, Superfund Research Program designed to further their interest in science, Tragic episodes of human exposure to 2015). These modules are based on a “train mathematics, or engineering. toxic chemicals have resulted from the migra- the trainer” model and provide information The KC Donnelly Externship Award, tion of the chemical manufacturing industry to communities on how to understand and named in honor of Kirby Cornwall (KC) and toxic chemicals to developing countries. reduce exposures to toxicants. Donnelly (1951–2009) of Texas A&M These include acute episodes such as the University, provides opportunities for current Bhopal disaster in India, where thousands of Conclusion SRP-funded graduate students and postdoc- people of all ages died or were severely injured The NIEHS SRP program was created 25 years toral researchers to compete for translational after exposure to methyl isocyanate released ago in response to a crisis­—the discovery that externships outside of their home universi- by an explosion in a pesticide manufacturing hazardous waste was a major and previously ties. Donnelly was professor and head of facility (Dhara et al. 2002), as well as chronic, unrecognized threat to human health and the Department of Environmental and slowly unfolding tragedies such as the current the environment. That threat remains, and Occupational Health, and Associate Director exposure of > 1 million persons in China, it is now spreading from the United States, of the Texas A&M SRP. As leader of the South and Southeast Asia, and sub-Saharan Japan, Australia, and Western Europe to South Texas Environmental Education and Africa to chrysotile asbestos (Frank and low- and middle-income countries, where it Research (STEER) program, he helped bridge Joshi 2014). is an increasingly important, but insufficiently the gap between public health and medicine In industrially developed as well as devel- recognized, risk factor for disease. for > 500 students (University of Texas Health oping countries, the populations at greatest In the years since its founding, SRP has Science Center at San Antonio 2015). In his risk of exposure to toxic chemicals are those grown modestly in size and greatly in scien- environmental research on the U.S.–Mexico who live or work near polluting industries and tific credibility and real-world impact. SRP is

Environmental Health Perspectives • volume 123 | number 10 | October 2015 915 Landrigan et al. a small program, but it has had an outsized References Denison MS, Phelan D, Elferink CJ. 1998. The Ah scientific influence. Its record is one of signifi- receptor signal transduction pathway. In: Toxicant– cant scientific achievements accomplished Ahsan H, Chen Y, Parvez F, Argos M, Hussain AI, Receptor Interactions: Modulation of Signal Transduction and Gene Expression (Denison MS, with extremely modest investment combined Momotaj H, et al. 2006. Health Effects of Arsenic Longitudinal Study (HEALS): description of a multi- Helferich WG, eds). Philadelphia, PA:Taylor and with clever leveraging of resources from many disciplinary epidemiologic investigation. J Expo Francis, 3–33. sources. The program has been extraordinarily Sci Environ Epidemiol 16:191–205. Dhara VR, Dhara R, Acquilla SD, Cullinan P. 2002. effective in facilitating research innovation, in Alshawabkeh A, Mao X. 2012. 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Available: http://www.edenspace.com/home/ stand out. arsenic. Environ Health Perspect 114:1193–1198; phytoremediation/ [accessed 9 December 2014]. The first is the fact that SRP provides doi:10.1289/ehp.9008. Escudero-Lourdes C, Medeiros MK, Cárdenas- González MC, Wnek SM, Gandolfi JA. 2010. Low targeted funds to investigate the health effects Argos M, Kalra T, Rathouz PJ, Chen Y, Pierce B, Parvez F, et al. 2010. Arsenic exposure from drinking level exposure to monomethyl arsonous acid- of hazardous waste—an area of scientific water, and all-cause and chronic-disease mortali- induced the over-production of inflammation- investigation that otherwise would likely ties in Bangladesh (HEALS): a prospective cohort related cytokines and the activation of cell signals be neglected. study. Lancet 376(9737):252–258; doi:10.1016/ associated with tumor progression in a urothelial The second is the program’s base in a S0140-6736(10)60481-3. cell model. 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JAMA Pediatr 168(1):61–67. of the nation’s best minds to focus on complex Center disaster and intrauterine growth restriction Frank AL, Joshi TK. 2014. The global spread of asbestos. Ann Glob Health 80(4):257–262. problems relevant to hazardous waste. [Letter]. JAMA 290(5):595–596. Bissonnette SL, Haas A, Mann KK, Schlezinger JJ. Furlong CE, Cole TB, Jarvik GP, Pettan-Brewer C, The third critical factor is the program’s 2010. The role of CaMKII in calcium-activated Geiss GK, Richter RJ, et al. 2005. Role of paraox- unique transdisciplinary structure that brings death pathways in bone marrow B cells. Toxicol onase (PON1) status in pesticide sensitivity: genetic together biomedical researchers and engineers, Sci 118(1):108–118; doi:10.1093/toxsci/kfq256. and temporal determinants. Neurotoxicology ecologists, earth scientists, social scientists, Blacksmith Institute. 2013. Blacksmith Institute 26(4):651–659. and evolutionary biologists. Because of this Homepage. Available: http://www. 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Environ Health 13(1):50; for the 2020 goal: the need for better information and sound management to minimize chemical discipline could have achieved on its own. doi:10.1186/1476-069X-13-50. Brusseau ML, Carroll KC, Truex MJ, Becker DJ. 2013. risks. In: UNEP Year Book 2013: Emerging Issues Skilled and experienced leadership at Characterization and remediation of chlorinated in our Global Environment. Nairobi, Kenya: United NIEHS has been the fourth factor critical to volatile organic contaminants in the vadose zone: Nations Environment Programme, 37–51. the success of the SRP. Beginning with David an overview of issues and approaches. Vadose Gomaa A, Hu H, Bellinger D, Schwartz J, Tsaih SW, P. Rall, NIEHS Director at the time of the Zone J 12(4); doi:10.2136/vzj2012.0137. Gonzalez-Cossio T, et al. 2002. Maternal bone lead establishment of SRP, and extending through Callaghan WM, MacDorman MF, Rasmussen SA, as an independent risk factor for fetal neurotoxicity: a prospective study. Pediatrics 110(1 pt 1):110–118. all the successive Directors up to and including Qin C, Lackritz EM. 2006. The contribution of preterm birth to infant mortality rates in the United Gomez-Rubio P, Klimentidis YC, Cantu-Soto E, Meza- the present NIEHS Director, Linda Birnbaum, States. Pediatrics 118 (4):1566–1573. Montenegro MM, Billheimer D, Lu Z, et al. 2012. the SRP has enjoyed high-level support from Caravanos J, Clark E, Fuller R, Lambertson C. 2011. Indigenous American ancestry is associated with top management of NIEHS. Just as important Assessing worker and environmental chemical arsenic methylation efficiency in an admixed has been the long time leadership of SRP’s exposure risks at an e-waste recycling and disposal population of northwest Mexico. J Toxicol Environ founding Program Director, William Suk site in Accra, Ghana. J Health Pollution 1:16–25. Health A 75(1):36–49. Gomez-Rubio P, Roberge J, Arendell L, Harris RB, (Wilson 2014). Chatham-Stephens K, Caravanos J, Ericson B, Sunga-Amparo J, Susilorini B, Sharma P, et al. O’Rourke MK, Chen Z, et al. 2011. Association If past is prologue, SRP’s first 25 years 2013. Burden of disease from toxic waste sites between body mass index and arsenic methylation have provided a firm foundation in the face of in India, Indonesia, and the Philippines in 2010. efficiency in adult women from southwest U.S. an uncertain future for United States science. Environ Health Perspect 121:791–796; doi:10.1289/ and northwest Mexico. Toxicol Appl Pharmacol Whether we can continue to develop more ehp.1206127. 252(2):176–182. and better science to solve one of the world’s Cherednichenko G, Zhang R, Bannister RA, Timofeyev V, Gordon JD, Clark GC. 2005. Submission of XDS’s LUMI- CELL™ ER High-Throughput System for Screening most difficult problems remains to be seen. Li N, Fritsch EB, et al. 2012. Triclosan impairs ­excitation–contraction coupling and Ca2+ dynamics Estrogen-Like Chemicals for Review by ICCVAM. But the potential is there, and a quarter- in striated muscle. Proc Natl Acad Sci USA Available: http://ntp.niehs.nih.gov/iccvam/methods/ century of success has shown that the resolu- 109:14158–14163. endocrine/endodocs/iccvamsubmission28jan05.pdf tion of pressing environmental issues through Choi JH, Damm CJ, O’Donovan NJ, Sawyer RF, [accessed 7 December 2014]. outstanding science is highly feasible, even Koshland CP, Lucas D. 2005. Detection of lead in Gordon M, Choe N, Duffy J, Ekuan G, Heilman P, in these resource-scarce times, with the most soil with excimer laser fragmentation fluorescence Muiznieks I, et al. 1998. Phytoremediation of spectroscopy. Appl Spectrosc 59(2):258–261. trichloroethylene with hybrid poplars. Environ modest of investments. Health Perspect 106(suppl 4):1001–1004.

916 volume 123 | number 10 | October 2015 • Environmental Health Perspectives The NIEHS Superfund Research Program

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918 volume 123 | number 10 | October 2015 • Environmental Health Perspectives